00947A: Heritable and Sporadic Genetic Lesions in Canine Osteosarcoma

Grant Status: Closed

Grant Amount: $147,482.64
Matthew Breen, PhD; North Carolina State University
August 1, 2008 - November 30, 2011


Breed(s): Rottweiler, Golden Retriever
Research Program Area: Oncology
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Project Summary

In this study we recruited 140 cases of canine osteosarcoma, representing client owned dogs of various breeds. Of these, 123 cases were analyzed using genome-wide 1Mb spacing BAC array comparative genomic hybridization (aCGH) to reveal changes in DNA copy number that were recurrent in canine osteosarcoma. This study represents that largest single cohort of osteosarcoma patients evaluated using aCGH, including human studies. Our data showed that, as with human osteosarcoma, canine osteosarcoma typically presents with chaotic copy number profiles, comprising whole chromosome aneuploidy, single locus copy number aberrations and structural rearrangements. Overall, chromosomal regions were more likely to experience copy number gain than copy number loss; within the sample population seven chromosomes contained regions that experienced greater than 10% copy number loss, while 23 chromosomes experienced regions with a copy number gain frequency greater than 10%. Dog chromosome 23 appeared to be the least aberrant chromosome with little variation between patients. The majority of regions experiencing >10% aberration frequency of copy number change in canine OS were <5Mb in size, while regions with < 5% aberration frequency were generally larger in size. These finding were published in the Sept 2011 issue of Journal 'Genes, Chromosomes and Cancer'. Subsequent to that component of the study, we analyzed 23 of the canine cases using a CGH platform with considerably higher resolution. This new array comprised 180,000 probes (compared to the 2,100 probes on the earlier version) that provided 76 times the amount of data. Analysis of these 23 canine osteosarcoma cases concluded that a pattern of high genomic instability is maintained when increasing genomic resolution. As expected, the higher resolution analysis, however, identified several micro-regions (<500kb) of copy number changes that were shown to be comparable to what we observed in our parallel study of human osteosarcoma. Comparison of canine and human osteosarcoma aCGH data identified that the most frequent regional copy number gains and losses in our dog and human cases were shared, with remarkably similar frequencies. The incidence of these aberrations in both in human and dog OS suggest that these specific genes may be directly contributing to the cancer phenotype. Nine genes of interest were analyzed for altered expression levels; MYC, MEN1, CDKN2A/B, TERT, PTEN, RHOC, RUNX2, TSC2 and TUSC3. From a comparative perspective these genes have now been implicated to be associated with human osteosarcoma. Functional analysis of these genes identified several cellular pathways deregulated in osteosarcoma. A manuscript reporting the finding of our high resolution, comparative assessment of canine and human osteosarcoma is in the final stages of preparation and is scheduled for submission in early 2012. It is very clear from the data generated in thus study that human and dog OS share conserved DNA copy number aberrations. We identified that orthologous regions in humans and canines have similar types (gain and loss) and frequencies of aberrations in osteosarcoma. These data strongly support the conserved nature of osteosarcoma. These data are now being used to advance new areas of research that ultimately we hope will lead to improved therapies for our canine patients, and maybe even our human patients.


Angstadt, A. Y., Motsinger-Reif, A., Thomas, R., Kisseberth, W. C., Guillermo Couto, C., Duval, D. L., … Breen, M. (2011). Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: Signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes, Chromosomes and Cancer, 50(11), 859–874. https://doi.org/10.1002/gcc.20908
Angstadt, A. Y., Thayanithy, V., Subramanian, S., Modiano, J. F., & Breen, M. (2012). A genome-wide approach to comparative oncology: High-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genetics, 205(11), 572–587. https://doi.org/10.1016/j.cancergen.2012.09.005
Karlsson, E. K., Sigurdsson, S., Ivansson, E., Thomas, R., Elvers, I., Wright, J., … Lindblad-Toh, K. (2013). Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biology, 14(12), R132. https://doi.org/10.1186/gb-2013-14-12-r132
Sarver, A. L., Thayanithy, V., Scott, M. C., Cleton-Jansen, A.-M., Hogendoorn, P. C., Modiano, J. F., & Subramanian, S. (2013). MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma. Orphanet Journal of Rare Diseases, 8(1), 7. https://doi.org/10.1186/1750-1172-8-7
Scott, M. C., Sarver, A. L., Gavin, K. J., Thayanithy, V., Getzy, D. M., Newman, R. A., … Modiano, J. F. (2011). Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone, 49(3), 356–367. https://doi.org/10.1016/j.bone.2011.05.008

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